The early detection of lung cancer is critical to improving the mortality rate associated with lung cancer. Identification of biomarkers indicative of early stages of carcinogenesis is necessary for this goal to be realized This entails both identification of markers that are indicative of early cancer or, preferably, of lesions with high rates of progression to cancer and being able to assay these markers in easily (i.e., noninvasively) obtained body tissues. One approach to address the former issue is to determine the frequency of marker expression in early preneoplastic lesions. The specificity of markers that are aberrantly expressed during early carcinogenesis for lung cancer will then need to be determined. Subsequently, techniques for assaying those markers that are expressed early will need to be optimized. We propose to study patients at high risk for lung cancer (i.e., patients with suspicious masses being evaluated for lung cancer, survivors of early stage lung or head and neck cancer) with serial monitoring of sputum and bronchoscopically obtained material to assay for biomarker expression. Recent studies suggest that fluorescence bronchoscopy (LIFE-Lung system, Xillix Technologies Corp.) significantly increases the identification of premalignant lesions. We will therefore evaluate all patients with conventional and fluorescence bronchoscopy. The purpose of these studies is to determine the frequency of expression of multiple biomarkers in histologically atypical (potentially premalignant) lesions and to correlate this with expression in tumors. This will help to determine the potential suitability of any given marker for broader application in screening. Furthermore, expression will be assayed in multiple specimen types (sputum, bronchial washings, bronchial biopsies) to determine the optimal techniques and specimen types for future studies. A variety of biomarkers will be tested: dominant oncogenes (c- jun), recessive oncogenes (p53), cell cycle genes (cyclin D1), proliferation indices (PCNA), and growth factor receptors. Subsequent studies will include interventions such as 4-HPR, if available, or low dose 13-cis-retinoic acid. Biomarker expression will be assessed prior to intervention, after intervention, and 3 months after stopping intervention. This will serve to identify potential intermediate endpoint biomarkers for use in future clinical trials. Ultimately the success of early detection of cancer is dependent upon the ability to intervene successfully at an early stage to prevent the morbidity and mortality associated with cancer and standard therapy.